Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer

解码并靶向癌症中的 LKB1-AMPK 信号通路

基本信息

批准号：
10222594
负责人：
Reuben Shaw
金额：
$ 116.4万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222594
关键词：
5&apos -AMP-activated protein kinase Acetyl-CoA Carboxylase Autophagocytosis Biochemical Pathway Cancer Model Cell Line Cell Survival Cell physiology Cells Cellular Metabolic Process Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Consumption Disease Enzyme Inhibitor Drugs Enzymes Event Fatty Acids Genes Genetic Models Genetically Engineered Mouse Glucose Grant Growth Hereditary Malignant Neoplasm Homeostasis Human Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolism Modeling Molecular Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Nutrient Oncogenes Oxygen Pathway interactions Peutz-Jeghers Syndrome Phosphotransferases Play Primary Neoplasm Process Protein Biosynthesis Protein Kinase Protein-Serine-Threonine Kinases Proteome Proteomics Research Role STK11 gene Signal Pathway Signal Transduction Starvation Therapeutic Tumor Suppression Tumor Suppressor Proteins anticancer activity base cancer cell cancer therapy cancer type drug metabolism fatty acid oxidation genetic technology lipid biosynthesis lipogenesis inhibitor neoplastic cell new therapeutic target novel preclinical study preservation sensor treatment response tumor metabolism

项目摘要

Summary / Abstract Research over the past decade has begun to reveal several direct linkages between genes mutated in human cancer and genes that control cell metabolism. The LKB1 tumor suppressor is a serine/threonine kinase mutationally inactivated in the familial cancer disease Peutz-Jeghers Syndrome, as well as in ~25% of non-small cell lung cancers, making it the third most frequent gene altered in this cancer type, which is responsible for the most deaths by cancer each year. Thirteen years ago, the Shaw lab and others discovered that LKB1 directly phosphorylates the activation loop of the AMP-activated protein kinase (AMPK) and 12 related kinases. AMPK is a serine/threonine kinase that is activated by LKB1 under conditions of low cellular energy, such as those that accompany loss of nutrients, in particular glucose and oxygen. AMPK plays a highly conserved role as an energy sensor and acts to restore metabolic homeostasis on a cellular and ultimately organismal level by downregulating anabolic biosynthetic ATP- consuming processes (like protein and lipid biosynthesis), and upregulating catabolic ATP-restoring processes (like autophagy and fatty acid oxidation). Studies by the Shaw lab over the past decade have sought to: 1) understand the mechanistic basis for how AMPK reprograms growth and metabolism by decoding direct substrates of AMPK that mediate its downstream effects, and 2) identify new cancer therapy approaches based on their understanding of the rate-limiting nodes of metabolism and growth that AMPK endogenously utilizes under low energy conditions. The Shaw lab has used a number of genetically engineered mouse models of non-small cell lung cancer to perform preclinical studies with novel cancer metabolism drugs, and this grant builds upon their expertise accumulated over the past decade. Three lines of research are proposed. First, advances in proteomics and genetic technologies will be used by the Shaw lab to conduct phospho-proteome screens in primary tumors that are with or without intact LKB1 to identify relevant targets required for tumor suppression in lung. These events will be rapidly modeled genetically in cell lines and ultimately in murine cancer models using CRISPR. Second, based on their understanding of how AMPK inhibits growth, the Shaw lab has explored the use of direct inhibitors of the lipogenesis enzyme Acetyl-CoA carboxylase (ACC) and found broad anti-cancer activity in genetic models of lung cancer. This proposal seeks to examine whether other fatty acid synthesis enzymes may offer therapeutic windows in lung cancer. Third, this proposal will explore the role of AMPK and its target the autophagy kinase ULK1 in promoting tumor cell survival, particularly in the context of therapeutic response. Altogether, these studies emphasize the need to gain a deep understanding of the molecular wiring of this signaling network and how it interfaces with key cellular processes in order to reveal novel vulnerabilities that can be exploited to selectively kill cancer cells.

摘要/摘要过去十年的研究已经开始揭示突变基因之间的一些直接联系。人类癌症和控制细胞代谢的基因。 LKB1 肿瘤抑制因子是丝氨酸/苏氨酸家族性癌症疾病黑斑息肉综合征以及约 25% 的患者中激酶突变失活的非小细胞肺癌，使其成为这种癌症类型中第三个最常见的基因改变，每年因癌症死亡人数最多。十三年前，Shaw 实验室和其他人发现LKB1直接磷酸化AMP激活蛋白激酶的激活环 (AMPK) 和 12 种相关激酶。 AMPK 是一种丝氨酸/苏氨酸激酶，在 LKB1 作用下被激活细胞能量低的情况，例如伴随营养物质损失的情况，特别是葡萄糖和氧。 AMPK 作为能量传感器发挥高度保守的作用，并起到恢复代谢的作用通过下调合成代谢生物合成 ATP，在细胞和最终有机体水平上实现稳态消耗过程（如蛋白质和脂质生物合成），以及上调分解代谢 ATP 恢复过程（如自噬和脂肪酸氧化）。 Shaw实验室过去十年的研究表明试图：1）了解 AMPK 如何通过以下方式重编程生长和代谢的机制基础：解码 AMPK 介导其下游效应的直接底物，以及 2) 确定新的癌症疗法基于他们对 AMPK 代谢和生长限速节点的理解的方法在低能量条件下内源利用。 Shaw 实验室使用了许多基因工程化非小细胞肺癌小鼠模型以对新型癌症进行临床前研究代谢药物，这项资助建立在他们过去十年积累的专业知识的基础上。三行提出了研究建议。首先，Shaw 将利用蛋白质组学和基因技术的进步实验室对具有或不具有完整 LKB1 的原发性肿瘤进行磷酸化蛋白质组筛选，以识别肺部肿瘤抑制所需的相关靶点。这些事件将在基因中快速建模细胞系，并最终使用 CRISPR 在小鼠癌症模型中。其次，根据自己的理解为了了解 AMPK 如何抑制生长，Shaw 实验室探索了使用脂肪生成酶的直接抑制剂乙酰辅酶A羧化酶（ACC）在肺癌遗传模型中发现了广泛的抗癌活性。这该提案旨在研究其他脂肪酸合成酶是否可以提供治疗窗口肺癌。第三，本提案将探讨 AMPK 及其靶标自噬激酶 ULK1 在促进肿瘤细胞存活，特别是在治疗反应的情况下。总而言之，这些研究强调需要深入了解该信号网络的分子线路以及如何它与关键的细胞过程交互，以揭示可被利用的新漏洞选择性杀死癌细胞。